Abstract-Reduction in uterine perfusion and the ensuing placental ischemia during late pregnancy have been proposed to trigger increases in systemic vascular resistance and pregnancy-induced hypertension; however, the intermediary mechanisms involved are unclear. The purpose of the present study was to test the hypothesis that reduced uterine perfusion pressure during late pregnancy is associated with impaired endothelium-dependent vascular relaxation and, consequently, enhanced systemic vascular reactivity. Active stress was measured in aortic strips isolated from late pregnant Sprague-Dawley rats and a hypertensive pregnant rat model produced through the long-term reduction in uterine perfusion pressure (RUPP). Phenylephrine (Phe, 10 Ϫ5 mol/L) caused an increase in active stress to 4.5Ϯ0.4ϫ10 3 N/m 2 in normal pregnant rats and a larger increase to 9.4Ϯ0.7ϫ10 3 N/m 2 in RUPP rats. Removal of the endothelium significantly enhanced Phe-induced stress in pregnant (6.4Ϯ0.6ϫ10 3 N/m 2 ) but not RUPP (9.95Ϯ0.95ϫ10 3 N/m 2 ) rats. In endothelium-intact strips, acetylcholine (ACh) was more potent in inducing relaxation of Phe contraction in pregnant (ED 50 0.1ϫ10 Ϫ6 mol/L) than in RUPP (ED 50 1.2ϫ10 Ϫ6 mol/L) rats. Pretreatment of endothelium-intact strips with N G -nitro-L-arginine methyl ester(100 mol/L), to inhibit nitric oxide (NO) synthase, significantly inhibited AChinduced relaxation and enhanced Phe-induced stress in pregnant (6.2Ϯ0.5ϫ10 3 N/m 2 ) but not RUPP (9.5Ϯ0.85ϫ10 3 N/m 2 ) rats. Pretreatment of endothelium-intact strips with methylene blue (10 mol/L), to inhibit cGMP production in smooth muscle, also inhibited ACh-induced relaxation and enhanced Phe-induced stress in pregnant (6.9Ϯ0.65ϫ10 3 N/m 2 ) but not RUPP (9.3Ϯ0.7ϫ10 3 N/m 2 ) rats. In endothelium-denuded strips, relaxation of Phe contraction with the exogenous NO donor sodium nitroprusside was not significantly different between pregnant and RUPP rats. These results suggest that an endothelium-dependent relaxation pathway involving the release of NO from endothelial cells and increased cGMP production in smooth muscle is inhibited in systemic vessels of late pregnant rats with reduced uterine perfusion pressure and may in part explain the increased vascular resistance in pregnancy-induced hypertension. Key Words: arteries Ⅲ blood pressure Ⅲ endothelium Ⅲ nitric oxide Ⅲ muscle, smooth, vascular N ormal pregnancy is often associated with reduction in systemic vascular resistance and arterial blood pressure and decreased vascular reactivity to circulating vasoconstrictors. [1][2][3][4] The hemodynamic and vascular changes observed during normal pregnancy have been explained in part by increased nitric oxide (NO) synthesis by various cells, including vascular endothelial cells. [5][6][7][8][9] This is supported by reports that the metabolic production and plasma level of cGMP, a second messenger of NO and a cellular mediator of vascular smooth muscle relaxation, 10,11 are increased during pregnancy. 12 In 5% to 7% of pregnancies, women develop a...

Abstract-The clinical observation that coronary artery disease is more common in men and postmenopausal women than in premenopausal women has suggested cardioprotective effects of female sex hormones including hormone-mediated coronary vasodilation. The purpose of this study was to investigate whether the sex hormone-induced coronary relaxation is caused by inhibition of Ca 2ϩ mobilization into coronary smooth muscle. Key Words: sex hormones Ⅲ calcium Ⅲ coronary Ⅲ contraction C oronary artery disease is one of the most common and costly diseases. Coronary vasospasm and subsequent occlusion are frequently associated with increased cardiovascular risk and may lead to myocardial infraction and death. 1 Clinical data suggest that the incidence of coronary heart disease is greater in men and postmenopausal women compared with premenopausal women. This is believed to be because of putative cardioprotective effects of the female sex hormone estrogen. The cardioprotective effects of estrogen have been explained by several mechanisms, including modification of lipid and carbohydrate metabolism, 2 modification of the composition of circulating lipoproteins, 3-5 and changes in blood coagulation, 6 as well as direct cardiovascular protective effects on hemodynamics. 7 Estrogens are vasodilators. For example, it has been reported that subcutaneous administration of ␤-estradiol in female guinea pigs reversibly and significantly lowers both the resting systolic blood pressure and the peak systolic blood pressure induced by a pressor challenge of norepinephrine. 8 Also intravenous infusion of estrogen in ovariectomized nonpregnant sheep has been shown to cause a significant increase in cardiac output and a decrease in systemic vascular resistance whereas local application of estrogen to the uterine artery only causes uterine vasodilation and increased uterine blood flow. 9 The vasodilator effects of estrogen have also been observed in normal coronary arteries. 10 The vascular endothelium has been suggested to play a role in mediating the estrogen-induced vasodilation. However, indomethacin does not affect the 17␤-estradiol-induced relaxation in endothelium-intact coronary arteries, 10 indicating that the release of vasodilator prostanoids is not involved in the 17␤-estradiol-induced coronary relaxation in vitro. Furthermore, estrogen causes vasodilation in deendothelialized rabbit coronary artery precontracted by endothelin-1, prostaglandin F 2␣ (PGF 2␣ ), and high-potassium depolarizing solution 10 suggesting that the estrogen-induced inhibition of vascular tone has an endothelium-independent component that involves direct action on vascular smooth muscle. 5,11,12

Abstract-Pregnancy-induced hypertension has been suggested to be mediated by several mechanisms, including reduced nitric oxide (NO) synthesis. In this study, the effects of chronic treatment with the NO synthase inhibitor N G -nitro-L-arginine methyl ester (L-NAME) on blood pressure and the underlying changes in vascular reactivity were investigated in virgin and late-pregnancy Sprague-Dawley rats. The systolic blood pressure was 120Ϯ2, 124Ϯ5, 116Ϯ4, and 171Ϯ5 mm Hg in untreated virgin, virgin treated with L-NAME, untreated pregnant, and pregnant treated with L-NAME rats, respectively. The rats were killed, and the thoracic aorta was cut into strips for measurement of active stress in response to ␣ 1 -adrenergic stimulation with phenylephrine and membrane depolarization by high KCl. In pregnant rats, the maximal active stress to phenylephrine (0.31Ϯ0.03ϫ104 N/m 2 ) and the high-KCl-induced active stress (0.55Ϯ0.09ϫ10 4 N/m 2 ) were smaller than those in virgin rats. By contrast, in the L-NAME-treated pregnant rats, the maximal phenylephrine-induced active stress (0. 76Ϯ0.1ϫ10 4 N/m 2 ) was greater than that in virgin rats (0.52Ϯ0.1ϫ10 4 N/m 2 ), whereas the high-KCl-induced active stress (1.08Ϯ0.14ϫ10 4 N/m 2 ) was indistinguishable from that in virgin rats (1. 03Ϯ0.14ϫ10 4 N/m 2 ). Treatment with L-NAME did not affect the phenylephrine-releasable Ca 2ϩ stores in pregnant rats and had minimal effect on active stress in virgin rats. Thus, reduction of NO synthesis during late pregnancy is associated with a significant increase in blood pressure and vascular responsiveness to ␣-adrenergic stimulation, which can possibly be explained in part by enhanced Ca 2ϩ entry from extracellular space. However, other mechanisms such as increased myofilament force sensitivity to Ca 2ϩ and/or activation of a completely Ca 2ϩ -independent mechanism cannot be excluded. (Hypertension. 1998;31:1065-1069.) Key Words: blood pressure Ⅲ calcium Ⅲ muscle, smooth Ⅲ contraction N ormal pregnancy is associated with many hemodynamic changes such as increased heart rate and cardiac output, 1 increased plasma volume, and an increase in uterine 2-4 and renal blood flow.5 Despite the increase in heart rate, blood volume, and cardiac output, normal pregnancy is usually associated with a significant decrease in arterial blood pressure and total peripheral resistance. 6 This normal pregnancyassociated decrease in peripheral resistance has been explained by several mechanisms, including an increase in the metabolic requirements of both maternal and fetoplacental tissues and/or a decrease in vascular reactivity. 7 Several explanations have been proposed for the decrease in vascular reactivity during normal pregnancy, such as decreased pressor response to vasoconstrictors, 8 -10 specific alterations within the vascular wall, 11 and an increase in nitric oxide (NO) synthesis.12,13 Also, Conrad and Vernier 14 have found that the plasma level, metabolic production, and urinary excretion of cGMP, a second messenger of NO and a cellular mediator of va...

1. The clinical observation that hypertension is more common in males and postmenopausal women than in premenopausal women suggests vascular protective effects of female sex hormones, including hormone-mediated inhibition of vascular tone. The purpose of the present study was to investigate whether the Ca2+ mobilization mechanisms of vascular smooth muscle contraction are modified by gender and sex hormones. 2. Active stress and [45Ca2+] influx were measured in de-endothelialized aortic strips isolated from intact and gonadectomized male and female Sprague-Dawley rats. In normal Krebs' (2.5 mmol/L Ca2+), both phenylephrine (Phe; 10(-5) mol/L) and membrane depolarization by 96 mmol/L KCl increased active stress to 15.5 +/- 1.3 x 10(3) and 14.8 +/- 1.2 x 10(3) N/m2, respectively, and Ca2+ influx to 28.4 +/- 1.4 and 32.3 +/- 1.5 mumol/kg per min, respectively, in intact males. The Phe- and KCl-induced stress and Ca2+ influx were significantly reduced in intact females. Gonadectomy was associated with no significant changes in the Phe- and KCl-induced stress and Ca2+ influx in males, but was associated with significant enhancement in females. In Ca(2+)-free (2 mmol/L EGTA) Krebs', stimulation of intracellular Ca2+ release by Phe or caffeine (25 mmol/L) caused a transient contraction that was not significantly different in all groups of rats. 3. Exogenous application of 17 beta-oestradiol, progesterone or testosterone to aortic strips caused concentration-dependent inhibition of Phe- and KCl-stimulated contractions and Ca2+ influx. 17 beta-Oestradiol was the most effective hormone and its relative potency was intact males, castrated males and ovariectomized females > intact females. 4. Thus, vascular reactivity and Ca2+ entry in aortic smooth muscle are reduced in the presence and enhanced in the absence of female gonads. Both male and female sex hormones cause vascular relaxation, mainly by inhibiting Ca2+ entry, with oestrogen being the most effective, particularly in the absence of female gonads. The results suggest that a cellular mechanism of oestrogen-induced vascular relaxation involving inhibition of Ca2+ entry into vascular smooth muscle is gender dependent.